Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability, thus leveraging the large investment in GWAS that produced so far little tangible gain.FCT: SFRH/BPD/64281/2009

Contributions to pegmatite exploration within granitic plutons in Central and Northern Portugal

Exploration programs for granitic pegmatites face the lack of detectable contrasts, either geophysical or geochemical, between pegmatites and their granitic host-rocks. The known productive sectors bearing pegmatites located inside granitic plutons, with economic interest for quartz and feldspar provide adequate field testing for alternative research, dealing with the peculiarities of lithological diversity and the arrangement of structural elements, around pegmatite swarms at suitable granite cupolas. The most efficient assessment for pegmatite positioning in tactical stages of exploration is the use of geological factors analyzed through raw or specifically treated remote imagery, enhancing the favorable lineaments and the most productive granite-host matrixes. The identification of targets using this approach led to a reasonable success tested by experimental drilling in some selected sites

Rethinking the Niche of Upper-Atmosphere Bacteria: Draft Genome Sequences of Bacillus aryabhattai C765 and Bacillus aerophilus C772, Isolated from Rice Fields

Here, we report two genome sequences of endospore-forming bacteria isolated from the rice fields of Comporta, Portugal, identified as Bacillus aryabhattai C765 and Bacillus aerophilus C772. Both species were previously identified in air samples from the upper atmosphere, but our findings suggest their presence in a wider range of environmental niches.FCT grant: (PEST-E/EQB/LA0004/2011), FCT contracts: (IF/00268/2013/CP1173/CT00061, SFRH/BPD/89907/2012)

Bioinformatics Projects Supporting Life-Sciences Learning in High Schools

The interdisciplinary nature of bioinformatics makes it an ideal framework to develop activities enabling enquiry-based learning. We describe here the development and implementation of a pilot project to use bioinformatics-based research activities in high schools, called "Bioinformatics@school." It includes web-based research projects that students can pursue alone or under teacher supervision and a teacher training program. The project is organized so as to enable discussion of key results between students and teachers. After successful trials in two high schools, as measured by questionnaires, interviews, and assessment of knowledge acquisition, the project is expanding by the action of the teachers involved, who are helping us develop more content and are recruiting more teachers and schools.Instituto Gulbenkian de Ciênci

inTB - a data integration platform for molecular and clinical epidemiological analysis of tuberculosis

This deposit is composed by the main article plus the supplementary materials of the publication.Tuberculosis is currently the second highest cause of death from infectious diseases worldwide. The emergence of multi and extensive drug resistance is threatening to make tuberculosis incurable. There is growing evidence that the genetic diversity of Mycobacterium tuberculosis may have important clinical consequences. Therefore, combining genetic, clinical and socio-demographic data is critical to understand the epidemiology of this infectious disease, and how virulence and other phenotypic traits evolve over time. This requires dedicated bioinformatics platforms, capable of integrating and enabling analyses of this heterogeneous data.Instituto Gulbenkian de Ciência, Programa Nacional de Luta contra a Tuberculose, Instituto Nacional de Saúde Ricardo Jorge, Administração Regional de Saúde de Lisboa e Vale do Tejo

Genetic Competence Drives Genome Diversity in Bacillus subtilis

This deposit is composed by the main article plus the supplementary materials of the publication.Prokaryote genomes are the result of a dynamic flux of genes, with increases achieved via horizontal gene transfer and reductions occurring through gene loss. The ecological and selective forces that drive this genomic flexibility vary across species. Bacillus subtilis is a naturally competent bacterium that occupies various environments, including plant-associated, soil, and marine niches, and the gut of both invertebrates and vertebrates. Here, we quantify the genomic diversity of B. subtilis and infer the genome dynamics that explain the high genetic and phenotypic diversity observed. Phylogenomic and comparative genomic analyses of 42 B. subtilis genomes uncover a remarkable genome diversity that translates into a core genome of 1,659 genes and an asymptotic pangenome growth rate of 57 new genes per new genome added. This diversity is due to a large proportion of low-frequency genes that are acquired from closely related species. We find no gene-loss bias among wild isolates, which explains why the cloud genome, 43% of the species pangenome, represents only a small proportion of each genome. We show that B. subtilis can acquire xenologous copies of core genes that propagate laterally among strains within a niche. While not excluding the contributions of other mechanisms, our results strongly suggest a process of gene acquisition that is largely driven by competence, where the long-term maintenance of acquired genes depends on local and global fitness effects. This competence-driven genomic diversity provides B. subtilis with its generalist character, enabling it to occupy a wide range of ecological niches and cycle through them.Fundação para a Ciência e a Tecnologia grants: (PTDC/EBB-BIO/119006/2010, PEst-OE/EQB/LA0004/2011, SFRH/BPD/89907/2012, SFRH/BD/29397/06); FEDER grant: (LISBOA-01-0145-FEDER-007660).info:eu-repo/semantics/publishedVersio

A functional analysis to differentiate pathogenic from benign variants identified in clinical diagnostic panels for breast cancer

Genetic testing for susceptibility genes through next‑generation sequencing (NGS) has become a widely used technique. Using this, a number of genetic variants have been identified, several of which are variants of unknown significance (VUS). These VUS can either be pathogenic or benign. However, since their biological effect remains unclear, functional assays are required to classify their functional nature. As the use of NGS becomes more mainstream as a diagnostic tool in clinical practice, the number of VUS is expected to increase. This necessitates their biological and functional classification. In the present study, a VUS was identified in the BRCA1 gene (NM_007294.3:c.1067A>G) in two women at risk for breast cancer, for which no functional data has been reported. Therefore, peripheral lymphocytes were isolated from the two women and also from two women without the VUS. DNA from all samples were sequenced by NGS of a breast cancer clinical panel. Since the BRCA1 gene is involved in DNA repair and apoptosis, the functional assays chromosomal aberrations, cytokinesis‑blocked micronucleus, comet, γH2AX, caspase and TUNEL assays were then conducted on these lymphocytes after a genotoxic challenge by ionizing radiation or doxorubicin to assess the functional role of this VUS. The micronucleus and TUNEL assays revealed a lower degree of DNA induced‑damage in the VUS group compared with those without the VUS. The other assays showed no significant differences between the groups. These results suggested that this BRCA1 VUS is likely benign, since the VUS carriers were apparently protected from deleterious chromosomal rearrangements, subsequent genomic instability and activation of apoptosis.publishersversionpublishe

Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells

This deposit is composed by the main article and supplementary files of the publication.Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.Bloomington Drosophila Stock Centre; Vienna Drosophila Research Center (VDRC); Developmental Studies Hybridoma Bank (DSHB); Fundação para a Ciência e Tecnologia (FCT) grant: (IF/01031/2012); Laço Grant in breast cancer 2015; Alexander von Humboldt Foundation grant: (Alexander von Humboldt Professorship); Liga Portuguesa contra o Cancro/Pfizer.info:eu-repo/semantics/publishedVersio

Is gut microbiota the key?

Funding: This study was supported by ERDF through the operation POCI-01-0145-ERDF-007746 funded by Programa Operacional Competitividade e Internacionalização—COMPETE2020 and by National Funds through FCT—Fundação para a Ciência e a Tecnologia within CINTESIS, R&D Unit (reference UID/IC/4255/2013) and CHRC (UIDB/04923/2020 and UIDP/04923/2020). This study was also supported by Emilio Peres grant from the Portuguese Society of Diabetology.The Mediterranean diet (MD) has been recommended for type 2 diabetes (T2D) treatment. The impact of diet in shaping the gut microbiota is well known, particularly for MD. However, the link between MD and diabetes outcome improvement is not completely clear. This study aims to evaluate the role of microbiota modulation by a nonpharmacological intervention in patients with T2D. In this 12-week single-arm pilot study, nine participants received individual nutritional counseling sessions promoting MD. Gut microbiota, biochemical parameters, body composition, and blood pressure were assessed at baseline, 4 weeks, and 12 weeks after the intervention. Adherence to MD [assessed by Mediterranean Diet Adherence Screener (MEDAS) score] increased after the intervention. Bacterial richness increased after 4 weeks of intervention and was negatively correlated with fasting glucose levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Prevotella to Bacteroides ratio also increased after 4 weeks. In contrast, glycated haemoglobin (HbA1c) and HOMA-IR were only decreased at the end of study. Alkaline phosphatase activity was assessed in fecal samples and was negatively correlated with HbA1c and positively correlated with bacterial diversity. The results of this study reinforce that MD adherence results in a better glycemic control in subjects with T2D. Changes in gut bacterial richness caused by MD adherence may be relevant in mediating the metabolic impact of this dietary intervention.publishersversionpublishe

A Gene Expression Signature to Select Hepatocellular Carcinoma Patients for Liver Transplantation

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.OBJECTIVE: To propose a new decision algorithm combining biomarkers measured in a tumor biopsy with clinical variables, to predict recurrence after liver transplantation (LT). SUMMARY BACKGROUND DATA: Liver cancer is one of the most frequent causes of cancer-related mortality. LT is the best treatment for hepatocellular carcinoma (HCC) patients but the scarcity of organs makes patient selection a critical step. Additionally, clinical criteria widely applied in patient eligibility decisions miss potentially curable patients while selecting patients that relapse after transplantation. METHODS: A literature systematic review singled out candidate biomarkers whose RNA levels were assessed by quantitative PCR in tumor tissue from 138 HCC patients submitted to LT (>5 y follow up, 32% beyond Milan criteria). The resulting four gene signature was combined with clinical variables to develop a decision algorithm using machine learning approaches. The method was named HepatoPredict. RESULTS: HepatoPredict identifies 99% disease-free patients (>5 y) from a retrospective cohort, including many outside clinical criteria (16%-24%), thus reducing the false negative rate. This increased sensitivity is accompanied by an increased positive predictive value (88,5%-94,4%) without any loss of long-term overall survival or recurrence rates for patients deemed eligible by HepatoPredict; those deemed ineligible display marked reduction of survival and increased recurrence in the short and long term. CONCLUSIONS: HepatoPredict outperforms conventional clinical-pathologic selection criteria, (Milan, UCSF) providing superior prognostic information. Accurately identifying which patients most likely benefit from LT enables an objective stratification of waiting lists and information-based allocation of optimal versus suboptimal organs.publishersversionepub_ahead_of_prin